Project Summary Environmental factors and lifestyle have profound effects in the initiation, promotion and progression of cancer. Our work on environmental enrichment (EE), a housing environment boosting mental health, has revealed a novel phenotype characterized by a robust reduction in adiposity, resistance to diet-induced obesity, lower leptin level, higher adiponectin level, enhanced immune functions, and marked inhibition in melanoma, breast, and colon cancer growth. Mechanistically, the physical, social and cognitive stimulations provided in EE stimulate hypothalamic brain-derived neurotrophic factor (BDNF) expression and thereby activates a specific neuroendocrine axis, hypothalamic-sympathoneural-adipocyte (HSA) axis leading to inhibition of leptin expression and release, as well as white fat browning. EE also enhances T cell immunity via both sympathetic nervous system (SNS) and the hypothalamic-pituitary- adrenal (HPA) axis. Both of the metabolic and immune modulations contribute to the antitumor effects of EE, and are orchestrated by the hypothalamic BDNF. Furthermore, our preliminary data suggest that EE induces adipose-resident natural killer (NK) cells likely also mediated by the HSA axis. The long-term goal of this project is to investigate how lifestyle and environmental factors regulate the development and function of adipose immune cells, and their implications in cancer prevention and treatment. We propose to test our hypothesis that environmental and genetic activation of the HSA axis induces adipose-resident NK cell through adipocyte-derived interleukin 15, which may have preventive and therapeutic significance of cancer. We plan to characterize the EE-induced regulation of adipose NK cells and elucidate the mechanisms in Aim 1. Specifically, the role of HSA axis will be investigated by both genetic (antagonizing hypothalamic BDNF signaling) and pharmacological approaches (?-adrenergic receptor agonist or antagonist). To assess whether adipocyte IL-15 is the key downstream mediator of the proposed brain-adipocyte-NK axis, we will use our novel adipose-specific recombinant adeno- associated viral vector to overexpress or knockdown IL-15 specifically in adipocytes. Moreover, we will study the preventive and therapeutic effects of EE-induced adipose NK cells on mammary tumor in the MMTV-PyMT spontaneous model as well as orthotopic and metastatic transplantation models of breast cancer in Aim 2. These studies will further characterize the brain-mediated anticancer effects, identify a novel brain-adipocyte-immune axis linking the beneficial adaptive responses to physical and social environments, and provide the preclinical data to assess the potential for ultimate clinical intervention.